Novel High Affinity Sigma-1 Receptor Ligands from Minimal Ensemble Docking-Based Virtual Screening.

Autor: Dvorácskó S; Biological Research Centre, Institute of Biochemistry, Eötvös Loránd Research Network (ELKH), H-6726 Szeged, Hungary., Lázár L; Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Hungary., Fülöp F; Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Hungary., Palkó M; Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Hungary., Zalán Z; Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Hungary., Penke B; Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Hungary., Fülöp L; Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Hungary., Tömböly C; Biological Research Centre, Institute of Biochemistry, Eötvös Loránd Research Network (ELKH), H-6726 Szeged, Hungary., Bogár F; Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Hungary.; MTA-SZTE Biomimetic Systems Research Group, Eötvös Loránd Research Network (ELKH), H-6720 Szeged, Hungary.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2021 Jul 29; Vol. 22 (15). Date of Electronic Publication: 2021 Jul 29.
DOI: 10.3390/ijms22158112
Abstrakt: Sigma-1 receptor (S1R) is an intracellular, multi-functional, ligand operated protein that also acts as a chaperone. It is considered as a pluripotent drug target in several pathologies. The publication of agonist and antagonist bound receptor structures has paved the way for receptor-based in silico drug design. However, recent studies on this subject payed no attention to the structural differences of agonist and antagonist binding. In this work, we have developed a new ensemble docking-based virtual screening protocol utilizing both agonist and antagonist bound S1R structures. This protocol was used to screen our in-house compound library. The S1R binding affinities of the 40 highest ranked compounds were measured in competitive radioligand binding assays and the sigma-2 receptor (S2R) affinities of the best S1R binders were also determined. This way three novel high affinity S1R ligands were identified and one of them exhibited a notable S1R/S2R selectivity.
Databáze: MEDLINE
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